The presence of obesity may confound cholecalciferol dosing in vitamin D-deficient patients owing to potentially decreased bioavailability. The aim of this retrospective study was to evaluate cholecalciferol therapy in vitamin D-deficient, critically ill trauma patients with and without obesity.Adult patients with severe traumatic injuries who had a serum 25-hydroxyvitamin D (25-OH vit D) <50nmol/L were prescribed 10 000 IU of liquid cholecalciferol daily. Efficacy was defined as achievement of a 25-OH vit D of 75 to 200nmol/L. Safety was evaluated by the presence of hypercalcemia (serum ionized calcium >1.32 mmol/L). Fifty-three patients (18 obese, 35 non-obese) were identified for study.Despite similar baseline concentrations (36 ± 7 versus 37 ± 7 nmol/L; P = NS), 25-OH vit D response was attenuated for those with obesity after 1 and 2 wk of cholecalciferol therapy (51 ± 18 versus 66 ± 27nmol/L, P < 0.01; 68 ± 19 versus 92 ± 25nmol/L, P < 0.01, respectively). Patients with obesity also tended to experience less hypercalcemia (22% versus 49% of patients, respectively) post-cholecalciferol therapy.Obesity alters the response to cholecalciferol therapy in critically ill patients with severe traumatic injuries.